[go: up one dir, main page]

US5486638A - Process for the preparation of 1-halo-3-trialkysilanyl-benzene derivatives - Google Patents

Process for the preparation of 1-halo-3-trialkysilanyl-benzene derivatives Download PDF

Info

Publication number
US5486638A
US5486638A US08/336,142 US33614294A US5486638A US 5486638 A US5486638 A US 5486638A US 33614294 A US33614294 A US 33614294A US 5486638 A US5486638 A US 5486638A
Authority
US
United States
Prior art keywords
temperature
suitable ether
process according
mixture
total amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US08/336,142
Inventor
Dennis K. Klipa
Robert T. Keaten
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MATION MERRELL DOW Inc
Dow Chemical Co
Aventis Pharmaceuticals Inc
Original Assignee
Marion Merrell Dow Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Marion Merrell Dow Inc filed Critical Marion Merrell Dow Inc
Priority to US08/336,142 priority Critical patent/US5486638A/en
Assigned to MATION MERRELL DOW INC. reassignment MATION MERRELL DOW INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DOW CHEMICAL COMPANY, THE
Assigned to DOW CHEMICAL COMPANY, THE reassignment DOW CHEMICAL COMPANY, THE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KEATEN, ROBERT T., KLIPA, DENNIS K.
Priority to AU38892/95A priority patent/AU695326B2/en
Priority to NZ295530A priority patent/NZ295530A/en
Priority to KR1019970703042A priority patent/KR970707134A/en
Priority to JP8515302A priority patent/JPH11501285A/en
Priority to HU9701329A priority patent/HUT76927A/en
Priority to FI971964A priority patent/FI971964L/en
Priority to MX9703368A priority patent/MX9703368A/en
Priority to PCT/US1995/012763 priority patent/WO1996014322A1/en
Priority to CA002204728A priority patent/CA2204728A1/en
Priority to EP95938151A priority patent/EP0791001A1/en
Priority to ZA959322A priority patent/ZA959322B/en
Priority to TW084111715A priority patent/TW349952B/en
Priority to AR33413495A priority patent/AR000246A1/en
Priority to IL11590795A priority patent/IL115907A0/en
Publication of US5486638A publication Critical patent/US5486638A/en
Application granted granted Critical
Priority to NO972129A priority patent/NO972129L/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/0827—Syntheses with formation of a Si-C bond

Definitions

  • the present invention relates to a novel process for preparing 1-halo-3-trialkylsilanyl-benzenes which are useful intermediates in the preparation of 1-(3-trialkylsilylphenyl)-2,2,2-trifluoromethyl ethanones which are useful for the treatment of Alzheimer's disease and senile dementia as disclosed by Schirlin, et al. in European Patent Application Publication No. 0 409 676, published Jan. 23, 1991.
  • the present invention provides a novel process for the preparation of a compound of the formula (I): ##STR1## wherein X 1 is Cl, Br or I; and
  • R 1 , R 2 and R 3 are each independently C 1 -C 4 alkyl, comprising adding a suitable ether to a mixture of ClSiR 1 R 2 R 3 , magnesium, a suitable aromatic solvent and a compound of the formula (II): ##STR2## wherein X 1 and X 2 are each independently Cl, Br or I and R 1 , R 2 and R 3 are defined as above; provided X 2 is other than Br or Cl when X 1 is I; and further provided X 2 is other than Cl when X 1 is Br.
  • C 1 -C 4 alkyl refers to a saturated straight or branched chain hydrocarbon radical of one to four carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
  • halo refers to a chlorine, bromine or iodine atom.
  • the dihalo compound of formula (II) is combined with magnesium, ClSiR 1 R 2 R 3 and a suitable aromatic solvent under an inert atmosphere, such as nitrogen. It is preferred that all reagents and starting materials be essentially anhydrous.
  • a dihalo compound of formula (II) are 1,3-dibromobenzene, 1,3-dichlorobenzene, 1-chloro-3-bromobenzene, 1,3-diiodobenzene, 1-chloro-3-iodobenzene and 1-bromo-3-iodobenzene, with the preferred dihalo compound of formula (II) being 1,3-dibromobenzene.
  • the total number of equivalents of magnesium employed in the process of Scheme I relative to the dihalo compound of formula (II) is from about 0.9 eq to about 1.1 eq, with about 1 eq being preferred.
  • magnesium suitable for Grignard reactions is preferred, such as magnesium powder, magnesium granules, magnesium ribbon, magnesium turnings and the like. Magnesium turnings are most preferred.
  • the reaction vessel is fitted with an agitator, such as a retreat curve agitator. The agitator is set at a speed sufficient for good mixing.
  • the total number of equivalents of ClSiR 1 R 2 R 3 employed in the process of Scheme I relative to the dihalo compound of formula (II) is from about 0.8 eq to about 1.2 eq, with about 1.1 eq being preferred.
  • Examples of ClSiR 1 R 2 R 3 are chlorotriethylsilane, chloro-tri-n-propylsilane, chloro-tri-n-butylsilane, chlorodimethylethylsilane, chlorodimethylisopropylsilane, chlorotrimethylsilane and the like. Chlorotrimethylsilane is the preferred ClSiR 1 R 2 R 3 .
  • the mass ratio of suitable aromatic solvent to dihalo compound of formula (II) employed in the process of Scheme I is from about 3 to about 10, with about 4.6 being preferred.
  • batch #2 810 lb of toluene are utilized with 176 lb of 1,3-dibromobenzene resulting in a mass ratio of 4.6 (810 lb/176 lb).
  • a suitable aromatic solvent are benzene, ethylbenzene, xylene, diethylbenzene, toluene and the like.
  • the preferred suitable aromatic solvent is toluene.
  • the above mixture is heated at a temperature of from about 20° C. to about 80° C. The preferred temperature of the mixture is about 50° C.
  • a suitable ether examples include diethyl ether, tetrahydropyran, tetrahydrofuran, and the like.
  • the preferred suitable ethers are tetrahydropyran and tetrahydrofuran, with tetrahydrofuran being most preferred.
  • the total number of equivalents of suitable ether employed in the process of Scheme I relative to the dihalo compound of formula (II) is from about 1.8 eq to about 4 eq, with about 2.5 eq of suitable ether being preferred.
  • the total amount of the suitable ether be added to the mixture in one portion initially, with about 10% of the total amount of the suitable ether being the preferred initial amount added to the mixture.
  • the remaining portion of the total amount of the suitable ether is then added at a rate of from about 0.15 eq/hour to about 2 eq/hour, with about 0.7 eq/hour to about 1.2 eq/hour being preferred and 1.13 eq/hour being the most preferred rate of addition of the suitable ether.
  • the controlled rate of addition of the remaining portion of the total amount of the suitable ether allows the temperature of the reaction to be controlled and essentially maintained at the mixture temperature, such as the preferred temperature of 50° C.
  • the temperature of the process of Scheme I be maintained at about 50° C. during addition of the suitable ether.
  • the reaction is allowed to stir for about 10 hours to about 15 hours at a temperature of from about 20° C. to about 70° C. with about 50° C. being the preferred temperature.
  • the slurry is then cautiously added to water which is at a temperature of from about 5° C. to about 50° C., with stirring.
  • the compound of formula (I) is then isolated and purified by techniques well known in the art, such as extractive methods, distillation, chromatography and the like. For example, the mixture is then stirred for about 10 minutes to about 1 hour.
  • the phases are then separated and the organic phase is optionally subjected to a second water wash.
  • the organic phase is then dried with a suitable drying agent, such as anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound of formula (I) which can be further purified by techniques well known in the art such as chromatography and/or vacuum distillation.
  • the organic phase is washed with water (50 mL), dried over anhydrous magnesium sulfate/sodium sulfate, filtered, concentrated under vacuum and distilled through a 40 theoretical plate concentric tube distillation column at 15 mm Hg.
  • the title compound is then collected at a temperature of from 94° C. to 105° C. to provide a colorless oil (32.7 g, 76.8%).
  • Reverse-phase HPLC (high performance liquid chromatography) analysis of the title compound can be performed utilizing a Hitachi Model L-6200 gradient pump, a Perkin-Elmer Diode Array 235 Detector, a Spectra-Physics Model 4270 integrator, a Hitachi Model AS-2000 autosampler, and a Rheodyne Model 7125 injector equipped with a 20 ⁇ L sample loop and a 4.0 ⁇ 80 mm Zorbax ODS (5 ⁇ m particles) column.
  • the detector is set at 255 nm, the mobile phase is 90:10 acetonitrile/water and the flow rate is set at 2 mL/min resulting in a retention time (R t ) for the title compound of about 0.92 to 0.95 minutes.
  • Preparative LC liquid chromatography
  • Preparative LC liquid chromatography
  • a Gilson Model 305 pump equipped with a Gilson Manometric Module Model 805, a Linear Model UV-106 (254nm) detector, a Sargent-Welch Model SRG-2 chart recorder, and a Rheodyne 7125 injector equipped with a 1.0 mL sample loop and an Alltech 22.5 ⁇ 250 mm Econosphere C 18 (10 ⁇ m particles) column.
  • the crude material is dissolved in acetonitrile prior to injection.
  • the detector is set at 254 nm, the mobile phase can be 90:10 or 85:15 acetonitrile/water and the flow rate is set at 15 mL/min resulting in an R t range for the title compound of about 8.5 to 11 minutes.
  • Gas chromatographic analysis of the title compound can be performed utilizing a Hewlett Packard 5890A Gas Chromatograph, a Hewlett Packard 7573A Autosampler fitted with a 10 ⁇ L syringe, a Hewlett Packard 7673 Autosampler Tray, a flame ionization detector, a PE-Nelson AccessChrom Rev. 1.9 with model 941 A/D data system, a Supelco SPB-1 30 m ⁇ 0.32 mm ID column with 1 ⁇ film thickness (cut from a 60 m column) and helium as the carrier gas.
  • the temperature gradient program used has an initial temperature of 60° C. that increases to 130° C. at a rate of about 16° C./min, it is then held at 130° C. for 12 min, and finally increased to 320° C. at a rate of about 22° C. /min at which time the run is terminated.
  • the retention time is approximately 16 min for 1-bromo-3-trimethytsilanyl-benzene.
  • Example 1a provides the general procedure followed for 10 separate batches for the large scale preparation of 1-bromo-3-trimethylsilanyl-benzene. Following Example 1a, Table 1 provides the individual amounts of reagents and starting materials utilized and the results obtained for each of the 10 batches.
  • the temperature control system of the reactor is set to maintain an internal reactor temperature of 50° C.
  • tetrahydrofuran 14 lb
  • the temperature of the reactor is monitored to determine when the reaction (exothermic) starts.
  • the reaction is determined to have started when the difference between the internal temperature of the reactor and the jacket temperature is greater than 5°-10° C.
  • tetrahydrofuran 130 lb
  • tetrahydrofuran 130 lb
  • the reactor contents are agitated for an additional 10-15 hours at 50° C.
  • the contents of the reactor are then transferred to a 300 gallon glass-lined reactor fitted with a pitched blade agitator and containing water (about 100 gallons at 5°-10° C. ).
  • Toluene (about 20 lb) is vacuum loaded into the original 200 gallon reactor and is used to flush the transfer line between the 200 gallon and 300 gallon reactors.
  • the 300 gallon reactor is agitated for about one hour, agitation is then stopped and the contents are allowed to settle for about 30-60 minutes.
  • the aqueous phase is then drained out of the 300 gallon reactor and water (about 25 gallons) is again added, followed by agitation for about 30 minutes.
  • the agitation is then stopped, the contents are allowed to settle for about 30-90 minutes and the aqueous layer is drained out of the 300 gallon reactor.
  • the organic phase is then drained to 55 gallon drums.
  • the 300 gallon reactor is then pressure tested, purged with nitrogen and about 1600-2000 lb of the above organic solution from the 55 gallon drums is vacuum loaded into the reactor.
  • the agitator is set at about 100 rpm and the jacket system set to hold the jacket temperature at 10°-20° C. above the internal temperature to begin distillation of the volatiles into a distillate receiver.
  • the distillation is continued until the internal temperature of the reactor reaches 68°-72° C.
  • the jacket temperature is then set to about 25° C. and the vacuum is broken with nitrogen.
  • the manway is opened and diatomaceous earth (about 20 lb) and magnesium sulfate (about 20 lb) are loaded into the reactor through the manway.
  • the manway is then closed and the reactor is pressure tested and purged with nitrogen.
  • the contents of the reactor are then drained into 55 gallon drums through a Nutsche filter (prepared by placing a new filter cloth in the bottom) to provide the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a novel process for preparing 1-halo-3-trialkylsilanyl-benzenes from 1,3-dihalo-benzenes which are useful intermediates in the preparation of 1-(3-trialkylsilylphenyl)-2,2,2-trifluoromethyl ethanones which are useful for the treatment of Alzheimer's disease and senile dementia.

Description

BACKGROUND OF THE INVENTION
The present invention relates to a novel process for preparing 1-halo-3-trialkylsilanyl-benzenes which are useful intermediates in the preparation of 1-(3-trialkylsilylphenyl)-2,2,2-trifluoromethyl ethanones which are useful for the treatment of Alzheimer's disease and senile dementia as disclosed by Schirlin, et al. in European Patent Application Publication No. 0 409 676, published Jan. 23, 1991.
SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation of a compound of the formula (I): ##STR1## wherein X1 is Cl, Br or I; and
R1, R2 and R3 are each independently C1 -C4 alkyl, comprising adding a suitable ether to a mixture of ClSiR1 R2 R3, magnesium, a suitable aromatic solvent and a compound of the formula (II): ##STR2## wherein X1 and X2 are each independently Cl, Br or I and R1, R2 and R3 are defined as above; provided X2 is other than Br or Cl when X1 is I; and further provided X2 is other than Cl when X1 is Br.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term "C1 -C4 alkyl" refers to a saturated straight or branched chain hydrocarbon radical of one to four carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like. As used herein the terms "halo", "halogen" or "halide" refer to a chlorine, bromine or iodine atom.
The process of the present invention is described in Scheme I. All the substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. ##STR3##
In Scheme I, a compound of formula (I) is prepared from a dihalo compound of formula (II) under the following conditions.
The dihalo compound of formula (II) is combined with magnesium, ClSiR1 R2 R3 and a suitable aromatic solvent under an inert atmosphere, such as nitrogen. It is preferred that all reagents and starting materials be essentially anhydrous. Examples of a dihalo compound of formula (II) are 1,3-dibromobenzene, 1,3-dichlorobenzene, 1-chloro-3-bromobenzene, 1,3-diiodobenzene, 1-chloro-3-iodobenzene and 1-bromo-3-iodobenzene, with the preferred dihalo compound of formula (II) being 1,3-dibromobenzene. The total number of equivalents of magnesium employed in the process of Scheme I relative to the dihalo compound of formula (II) is from about 0.9 eq to about 1.1 eq, with about 1 eq being preferred. In addition, magnesium suitable for Grignard reactions is preferred, such as magnesium powder, magnesium granules, magnesium ribbon, magnesium turnings and the like. Magnesium turnings are most preferred. The reaction vessel is fitted with an agitator, such as a retreat curve agitator. The agitator is set at a speed sufficient for good mixing. The total number of equivalents of ClSiR1 R2 R3 employed in the process of Scheme I relative to the dihalo compound of formula (II) is from about 0.8 eq to about 1.2 eq, with about 1.1 eq being preferred. Examples of ClSiR1 R2 R3 are chlorotriethylsilane, chloro-tri-n-propylsilane, chloro-tri-n-butylsilane, chlorodimethylethylsilane, chlorodimethylisopropylsilane, chlorotrimethylsilane and the like. Chlorotrimethylsilane is the preferred ClSiR1 R2 R3. The mass ratio of suitable aromatic solvent to dihalo compound of formula (II) employed in the process of Scheme I is from about 3 to about 10, with about 4.6 being preferred. For example, as described in Table 1, batch #2, 810 lb of toluene are utilized with 176 lb of 1,3-dibromobenzene resulting in a mass ratio of 4.6 (810 lb/176 lb). Examples of a suitable aromatic solvent are benzene, ethylbenzene, xylene, diethylbenzene, toluene and the like. The preferred suitable aromatic solvent is toluene. The above mixture is heated at a temperature of from about 20° C. to about 80° C. The preferred temperature of the mixture is about 50° C. When the temperature of the mixture begins to fall, the addition of a suitable ether is initiated. Examples of a suitable ether are diethyl ether, tetrahydropyran, tetrahydrofuran, and the like. The preferred suitable ethers are tetrahydropyran and tetrahydrofuran, with tetrahydrofuran being most preferred. The total number of equivalents of suitable ether employed in the process of Scheme I relative to the dihalo compound of formula (II) is from about 1.8 eq to about 4 eq, with about 2.5 eq of suitable ether being preferred. It is preferred that from about 2% to about 15% of the total amount of the suitable ether be added to the mixture in one portion initially, with about 10% of the total amount of the suitable ether being the preferred initial amount added to the mixture. The remaining portion of the total amount of the suitable ether is then added at a rate of from about 0.15 eq/hour to about 2 eq/hour, with about 0.7 eq/hour to about 1.2 eq/hour being preferred and 1.13 eq/hour being the most preferred rate of addition of the suitable ether. The controlled rate of addition of the remaining portion of the total amount of the suitable ether allows the temperature of the reaction to be controlled and essentially maintained at the mixture temperature, such as the preferred temperature of 50° C. It is preferred that the temperature of the process of Scheme I be maintained at about 50° C. during addition of the suitable ether. After addition of the total amount of suitable ether is complete, the reaction is allowed to stir for about 10 hours to about 15 hours at a temperature of from about 20° C. to about 70° C. with about 50° C. being the preferred temperature. The slurry is then cautiously added to water which is at a temperature of from about 5° C. to about 50° C., with stirring. The compound of formula (I) is then isolated and purified by techniques well known in the art, such as extractive methods, distillation, chromatography and the like. For example, the mixture is then stirred for about 10 minutes to about 1 hour. The phases are then separated and the organic phase is optionally subjected to a second water wash. The organic phase is then dried with a suitable drying agent, such as anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound of formula (I) which can be further purified by techniques well known in the art such as chromatography and/or vacuum distillation.
The following examples present typical syntheses as described in Scheme I. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "L" refers to liters; "ml" refers to milliliters; "bp" refers to boiling point; "mp" refers to melting point; "°C." refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "μL" refers to microliters; "μg" refers to micrograms; "μM" refers to micromolar; "eq" refers to equivalents; "min" refers to minutes; "rpm" refers to revolutions per minute; and "lb" refers to pounds.
EXAMPLE 1 Small scale preparation of 1-bromo-3-trimethylsilanyl-benzene. ##STR4##
Scheme Z; A 500 mL round-bottomed, 3 necked, fluted flask with a thermowell is fitted with an addition funnel, mechanical stirrer, reflux condenser and thermocouple recorder. The atmosphere is flushed with nitrogen. Magnesium (4.84 g, 0.199 mole), chlorotrimethylsilane (45.9 g, 0.422 mole), toluene (214 g) and 1,3-dibromobenzene (46.5 g, 0.197 mole) are then added. The mixture is heated to 50° C. with a heat gun and then allowed to slowly cool. When the temperature starts to fall, tetrahydrofuran (38.1 g) is added. The temperature continues to fall to 42° C. where it stabilizes and then begins to rise. The temperature is controlled at 50°±2° C. while the remaining tetrahydrofuran (342.9 g) is added dropwise (1 drop every 5 to 8 seconds) over a 2 hour period. When about 60-70% of the tetrahydrofuran has been added the exotherm subsides and a fluffy solid forms. The remainder of the tetrahydrofuran is added rapidly without evidence of an exotherm. The mixture is then allowed to cool to room temperature overnight. The slurry is vacuum transferred to a one liter flask containing water heated to 50° C. producing a temperature increase. The mixture is stirred for 10 minutes and the phases are separated (mixture temperature is 45° C. when separated). The organic phase is washed with water (50 mL), dried over anhydrous magnesium sulfate/sodium sulfate, filtered, concentrated under vacuum and distilled through a 40 theoretical plate concentric tube distillation column at 15 mm Hg. The title compound is then collected at a temperature of from 94° C. to 105° C. to provide a colorless oil (32.7 g, 76.8%).
Reverse-phase HPLC (high performance liquid chromatography) analysis of the title compound can be performed utilizing a Hitachi Model L-6200 gradient pump, a Perkin-Elmer Diode Array 235 Detector, a Spectra-Physics Model 4270 integrator, a Hitachi Model AS-2000 autosampler, and a Rheodyne Model 7125 injector equipped with a 20 μL sample loop and a 4.0×80 mm Zorbax ODS (5 μm particles) column. The detector is set at 255 nm, the mobile phase is 90:10 acetonitrile/water and the flow rate is set at 2 mL/min resulting in a retention time (Rt) for the title compound of about 0.92 to 0.95 minutes.
Preparative LC (liquid chromatography) of the title compound can be performed utilizing a Gilson Model 305 pump equipped with a Gilson Manometric Module Model 805, a Linear Model UV-106 (254nm) detector, a Sargent-Welch Model SRG-2 chart recorder, and a Rheodyne 7125 injector equipped with a 1.0 mL sample loop and an Alltech 22.5×250 mm Econosphere C18 (10 μm particles) column. The crude material is dissolved in acetonitrile prior to injection. The detector is set at 254 nm, the mobile phase can be 90:10 or 85:15 acetonitrile/water and the flow rate is set at 15 mL/min resulting in an Rt range for the title compound of about 8.5 to 11 minutes.
Gas chromatographic analysis of the title compound can be performed utilizing a Hewlett Packard 5890A Gas Chromatograph, a Hewlett Packard 7573A Autosampler fitted with a 10 μL syringe, a Hewlett Packard 7673 Autosampler Tray, a flame ionization detector, a PE-Nelson AccessChrom Rev. 1.9 with model 941 A/D data system, a Supelco SPB-1 30 m×0.32 mm ID column with 1μ film thickness (cut from a 60 m column) and helium as the carrier gas. The conditions used are a 10 psi column head pressure, a 105 mL/min split flow, a 1.8 mL/min column flow, 20 mL/min detector make up (nitrogen), 20 mL/min detector hydrogen flow, 300 mL/min detector air flow, detector range=2, injector temperature of 275° C. and a detector temperature of 300° C. The temperature gradient program used has an initial temperature of 60° C. that increases to 130° C. at a rate of about 16° C./min, it is then held at 130° C. for 12 min, and finally increased to 320° C. at a rate of about 22° C. /min at which time the run is terminated. The retention time is approximately 16 min for 1-bromo-3-trimethytsilanyl-benzene.
Example 1a provides the general procedure followed for 10 separate batches for the large scale preparation of 1-bromo-3-trimethylsilanyl-benzene. Following Example 1a, Table 1 provides the individual amounts of reagents and starting materials utilized and the results obtained for each of the 10 batches.
Example 1a Large scale preparation of 1-Bromo-3-trimethylsilanyl-benzene.
Scheme I, ; Magnesium turnings (18.25 lb) are loaded into a 200 gallon glass-lined reactor fitted with a retreat curve agitator. The reactor is sealed, pressure tested and purged with nitrogen. 1,3-dibromobenzene (176 lb) is then vacuum loaded into the reactor followed by vacuum loading of toluene (806.6 lb). The agitator is set to 130 rpm in order to obtain good mixing. Chlorotrimethylsilane (180 lb) is then loaded into the reactor by adding nitrogen pressure to the cylinder of chlorotrimethylsilane and opening the cylinder to the reactor headspace. After loading the chlorotrimethylsilane, the transfer line is blown clear with nitrogen. The temperature control system of the reactor is set to maintain an internal reactor temperature of 50° C. When the internal temperature and jacket temperature of the reactor stabilize at 50° C., tetrahydrofuran (14 lb) is pumped into the reactor headspace. The temperature of the reactor is monitored to determine when the reaction (exothermic) starts. The reaction is determined to have started when the difference between the internal temperature of the reactor and the jacket temperature is greater than 5°-10° C. After the reaction starts, tetrahydrofuran (130 lb) is pumped into the reactor at a rate of about 0.7 eq/hour to about 1.2 eq/hour. After addition of the tetrahydrofuran is complete, the reactor contents are agitated for an additional 10-15 hours at 50° C.
The contents of the reactor are then transferred to a 300 gallon glass-lined reactor fitted with a pitched blade agitator and containing water (about 100 gallons at 5°-10° C. ). Toluene (about 20 lb) is vacuum loaded into the original 200 gallon reactor and is used to flush the transfer line between the 200 gallon and 300 gallon reactors. The 300 gallon reactor is agitated for about one hour, agitation is then stopped and the contents are allowed to settle for about 30-60 minutes. The aqueous phase is then drained out of the 300 gallon reactor and water (about 25 gallons) is again added, followed by agitation for about 30 minutes. The agitation is then stopped, the contents are allowed to settle for about 30-90 minutes and the aqueous layer is drained out of the 300 gallon reactor. The organic phase is then drained to 55 gallon drums.
The 300 gallon reactor is then pressure tested, purged with nitrogen and about 1600-2000 lb of the above organic solution from the 55 gallon drums is vacuum loaded into the reactor. The agitator is set at about 100 rpm and the jacket system set to hold the jacket temperature at 10°-20° C. above the internal temperature to begin distillation of the volatiles into a distillate receiver. As the level in the reactor decreases, additional organic solution from the 55 gallon drums is loaded until 5 batches have been loaded into the reactor. The distillation is continued until the internal temperature of the reactor reaches 68°-72° C. The jacket temperature is then set to about 25° C. and the vacuum is broken with nitrogen. When the internal temperature of the reactor is less then about 35° C., the manway is opened and diatomaceous earth (about 20 lb) and magnesium sulfate (about 20 lb) are loaded into the reactor through the manway. The manway is then closed and the reactor is pressure tested and purged with nitrogen. The contents of the reactor are then drained into 55 gallon drums through a Nutsche filter (prepared by placing a new filter cloth in the bottom) to provide the title compound.
                                  TABLE 1                                 
__________________________________________________________________________
Summary of Reaction Conditions and % Yield of 1-Bromo-3-trimethylsilanyl- 
benzene for Ten Individual Batches Following the Procedure Described in   
Example 1 for                                                             
each Individual Batch in an Analogous Manner.                             
             #1 #2 #3 #4 #5 #6 #7 #8 #9 #10                               
                                           total                          
__________________________________________________________________________
Magnesium (lb)                                                            
             18.25                                                        
                18.25                                                     
                   18.25                                                  
                      18.25                                               
                         18.25                                            
                            18.25                                         
                               18.3                                       
                                  18.5                                    
                                     18.3                                 
                                        17.5                              
                                           182                            
1,3-Dibromobenzene (lb)                                                   
             176                                                          
                176                                                       
                   176                                                    
                      176                                                 
                         176                                              
                            176                                           
                               176                                        
                                  176                                     
                                     176.3                                
                                        168.9                             
                                           1753                           
Toluene (lb) 806.6                                                        
                810                                                       
                   811                                                    
                      812                                                 
                         810                                              
                            811                                           
                               810                                        
                                  810                                     
                                     814                                  
                                        780                               
                                           8075                           
Chlorotrimethylsilane (lb)                                                
             176                                                          
                180                                                       
                   178                                                    
                      159                                                 
                         176                                              
                            171                                           
                               172                                        
                                  215                                     
                                     177                                  
                                        138                               
                                           1742                           
Initial THF (lb)                                                          
             28 14 14 14 14 14 14 14 14.1                                 
                                        13.3                              
                                           153                            
Final THF (lb)                                                            
             116                                                          
                130                                                       
                   130                                                    
                      130                                                 
                         130                                              
                            130.1                                         
                               130                                        
                                  130                                     
                                     120                                  
                                        125                               
                                           1271                           
Total THF (lb)                                                            
             144                                                          
                144                                                       
                   144                                                    
                      144                                                 
                         144                                              
                            144.1                                         
                               144                                        
                                  144                                     
                                     144.1                                
                                        138.3                             
                                           1434.5                         
Time for final THF                                                        
             140                                                          
                180                                                       
                   140                                                    
                      145                                                 
                         145                                              
                            135                                           
                               160                                        
                                  194                                     
                                     210                                  
                                        215                               
addition (min)                                                            
Quench water (gal)                                                        
             100                                                          
                100                                                       
                   100                                                    
                      100                                                 
                         100                                              
                            100                                           
                               100                                        
                                  100                                     
                                     100                                  
                                        100                               
                                           1000                           
Toluene flush (lb)                                                        
             21.5                                                         
                20 20 20 20 20 20 28 20 21 211                            
Water wash (gal)                                                          
             25 25 25 25 25 25 25 25 25 25 250                            
Agitator speed (rpm)                                                      
             130.4                                                        
                130.8                                                     
                   130                                                    
                      110                                                 
                         110                                              
                            135                                           
                               133                                        
                                  135                                     
                                     132.5                                
                                        127                               
% yield of   64.58                                                        
                68.78                                                     
                   63.93                                                  
                      64.90                                               
                         63.53                                            
                            64.39                                         
                               64.35                                      
                                  63.40                                   
                                     66.20                                
                                        66.04                             
                                           65.0                           
1-Bromo-3-                                                                
trimethylsilanyl-benzene                                                  
__________________________________________________________________________
Example 2 Preparation of 1-Chloro-3-trimethylsilanyl-benzene. ##STR5##
Scheme I; 1-Chloro-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1-chloro-3-bromobenzene as the dihalo compound of formula (II).
Example 3 Preparation of 1-Bromo-3-trimethylsilanyl-benzene. ##STR6##
Scheme I; 1-Bromo-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1-bromo-3-iodobenzene as the dihalo compound of formula (II).
Example 4 Preparation of 1-Chloro-3-trimethylsilanyl-benzene. ##STR7##
Scheme I; 1-Chloro-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1-chloro-3-iodobenzene as the dihalo compound of formula (II).
Example 5 Preparation of 1-Iodo-3-trimethylsilanyl-benzene. ##STR8##
Scheme I; 1-Iodo-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1,3-diiodobenzene as the dihalo compound of formula (II).
Example 6 Preparation of 1-Bromo-3-triethylsilanyl-benzene. ##STR9##
Scheme I; 1-Bromo-3-triethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing 1,3-dibromobenzene and chlorotriethylsilane as the ClSiR1 R2 R3 compound.
Example 7 Preparation of 1-Bromo-3-tri-n-propylsilanyl-benzene. ##STR10##
Scheme I; 1-Bromo-3-tri-n-propylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing 1,3-dibromobenzene and chloro-tri-n-propylsilane as the ClSiR1 R2 R3 compound.
Example 8 Preparation of 1-Bromo-3-dimethylethylsilanyl-benzene. ##STR11##
Scheme I; 1-Bromo-3-dimethylethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing 1,3-dibromobenzene and chlorodimethylethylsilane as the ClSiR1 R2 R3 compound.
Example 9 Preparation of 1-Bromo-3-dimethylisopropylsilanyl-benzene. ##STR12##
Scheme I; 1-Bromo-3-dimethylisopropylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing 1,3-dibromobenzene and chlorodimethylisopropylsilane as the ClSiR1 R2 R3 compound.
Example 10 Preparation of 1-Bromo-3-tri-n-butylsilanyl-benzene. ##STR13##
Scheme I; 1-Bromo-3-tri-n-butylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing 1,3-dibromobenzene and chloro-tri-n-butylsilane as the ClSiR1 R2 R3 compound.

Claims (15)

What is claimed is:
1. A process for the preparation of a compound of the formula: ##STR14## wherein X1 is Cl Br or I; and
R1, R2 and R3 are each independently C1 -C4 alkyl, comprising adding a suitable ether to a mixture of ClSiR1 R2 R3, magnesium, a suitable aromatic solvent and a compound of the formula: ##STR15## wherein X1 and X2 are each independently Cl Br or I and R1, R2 and R3 are defined as above; provided X2 is other than Br or Cl when X1 is I; and further provided X2 is other than Cl when X1 is Br.
2. A process according to claim 1 wherein a total amount of about 2.5 equivalents of the suitable ether is added to the mixture.
3. A process according to claim 2 wherein about 10% of the total amount of the suitable ether is added to the mixture in one portion and the remaining 90% of the total amount of the suitable ether is then added at a rate of from about 0.15 eq/hour to about 2 eq/hour.
4. A process according to claim 2 wherein about 10% of the total amount of the suitable ether is added to the mixture in one portion and the remaining 90% of the total amount of the suitable ether is then added at a rate of from about 0.7 eq/hour to about 1.2 eq/hour.
5. A process according to claim 2 wherein about 10% of the total amount of the suitable ether is added to the mixture in one portion and the remaining 90% of the total amount of the suitable ether is then added at a rate of about 1.13 eq/hour.
6. A process as in one of claims 3-5 wherein the mixture is heated to a temperature of from about 20° C. to about 80° C. just prior to addition of the suitable ether.
7. A process as in one of claims 3-5 wherein the mixture is heated to a temperature of about 50° C. just prior to addition of the suitable ether.
8. A process according to claim 7 wherein the total number of equivalents of magnesium is from about 0.9 eq to about 1.1 eq.
9. A process according to claim 7 wherein the total number of equivalents of magnesium is about 1 eq.
10. A process according to claim 9 wherein the suitable ether is tetrahydrofuran.
11. A process according to claim 10 wherein the suitable aromatic solvent is toluene.
12. A process according to claim 11 wherein X1 and X2 are Br.
13. A process according to claim 12 wherein R1, R2 and R3 are each methyl.
14. A process according to claim 13 further comprising stirring the reaction at a temperature of from about 20° C. to about 70° C. for about 10 hours to 15 hours after addition of the total amount of the suitable ether is complete.
15. A process according to claim 14 wherein the reaction is stirred at a temperature of about 50° C. after addition of the total amount of the suitable ether is complete.
US08/336,142 1994-11-08 1994-11-08 Process for the preparation of 1-halo-3-trialkysilanyl-benzene derivatives Expired - Fee Related US5486638A (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
US08/336,142 US5486638A (en) 1994-11-08 1994-11-08 Process for the preparation of 1-halo-3-trialkysilanyl-benzene derivatives
NZ295530A NZ295530A (en) 1994-11-08 1995-10-04 Preparation of 1-halo-3-trialkylsilanyl-benzenes
MX9703368A MX9703368A (en) 1994-11-08 1995-10-04 Process for the preparation of 1-halo-3-trialkylsilanyl-benzene derivatives.
EP95938151A EP0791001A1 (en) 1994-11-08 1995-10-04 Process for the preparation of 1-halo-3-trialkylsilanyl-benzene derivatives
KR1019970703042A KR970707134A (en) 1994-11-08 1995-10-04 Process for the Preparation of 1-Halo-3-Trialkylsilanyl-Benzene Derivatives
JP8515302A JPH11501285A (en) 1994-11-08 1995-10-04 Method for producing 1-halo-3-trialkylsilanyl-benzene derivative
HU9701329A HUT76927A (en) 1994-11-08 1995-10-04 Process for the preparation of 1-halo-3- (trialkylsilyl) benzene derivatives
FI971964A FI971964L (en) 1994-11-08 1995-10-04 Process for the preparation of 1-halo-3-trialkylsilazylbenzene derivatives
AU38892/95A AU695326B2 (en) 1994-11-08 1995-10-04 Process for the preparation of 1-halo-3-trialkylsilanyl-benzene derivatives
PCT/US1995/012763 WO1996014322A1 (en) 1994-11-08 1995-10-04 Process for the preparation of 1-halo-3-trialkylsilanyl-benzene derivatives
CA002204728A CA2204728A1 (en) 1994-11-08 1995-10-04 Process for the preparation of 1-halo-3-trialkylsilanyl-benzene derivatives
ZA959322A ZA959322B (en) 1994-11-08 1995-11-03 Process for the preparation of 1-halo-3-trialkylsilanyl-benzene derivatives
TW084111715A TW349952B (en) 1994-11-08 1995-11-04 Process for the preparation of 1-halo-3-triaklylsilanyl-benzene derivatives
AR33413495A AR000246A1 (en) 1994-11-08 1995-11-07 Procedure for the preparation of derivatives of 1-halo-3-trialkylsilanyl-benzenes useful as intermediates in the preparation of 1- (3-trialkylsilylphenyl) -2,2,2-trifluoromethyl ethanones that are useful in the treatment of Alzheimer's disease senile dementia
IL11590795A IL115907A0 (en) 1994-11-08 1995-11-07 Process for the preparation of 1-halo-3-trialkylsilanyl-benzene derivatives
NO972129A NO972129L (en) 1994-11-08 1997-05-07 Process for the preparation of 1-halo-3-trialkylsilanyl-benzene derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08/336,142 US5486638A (en) 1994-11-08 1994-11-08 Process for the preparation of 1-halo-3-trialkysilanyl-benzene derivatives

Publications (1)

Publication Number Publication Date
US5486638A true US5486638A (en) 1996-01-23

Family

ID=23314759

Family Applications (1)

Application Number Title Priority Date Filing Date
US08/336,142 Expired - Fee Related US5486638A (en) 1994-11-08 1994-11-08 Process for the preparation of 1-halo-3-trialkysilanyl-benzene derivatives

Country Status (16)

Country Link
US (1) US5486638A (en)
EP (1) EP0791001A1 (en)
JP (1) JPH11501285A (en)
KR (1) KR970707134A (en)
AR (1) AR000246A1 (en)
AU (1) AU695326B2 (en)
CA (1) CA2204728A1 (en)
FI (1) FI971964L (en)
HU (1) HUT76927A (en)
IL (1) IL115907A0 (en)
MX (1) MX9703368A (en)
NO (1) NO972129L (en)
NZ (1) NZ295530A (en)
TW (1) TW349952B (en)
WO (1) WO1996014322A1 (en)
ZA (1) ZA959322B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0770618A3 (en) * 1995-10-23 1999-01-20 Dow Corning Corporation Process for preparation of organosilanes
US6380415B2 (en) * 2000-02-14 2002-04-30 Central Glass Company, Limited Process for producing octafluoro[2,2]paracyclophane
KR100979578B1 (en) * 2002-06-13 2010-09-01 다우 코닝 코포레이션 Process for preparing organosilanes and derivatives thereof by a novel Grignard process

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3080324A (en) * 1960-08-01 1963-03-05 Cincinnati Milling Machine Co Grignard reagents
US3347897A (en) * 1963-12-24 1967-10-17 Monsanto Res Corp Haloaryl organodisilaalkane compounds and use therefor
US4116993A (en) * 1977-07-05 1978-09-26 General Electric Company Process for producing aromatic-containing silicone compounds
EP0403713A1 (en) * 1989-06-22 1990-12-27 Merrell Dow Pharmaceuticals Inc. Novel acetylcholinesterase inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3726999A1 (en) * 1987-08-13 1989-02-23 Consortium Elektrochem Ind DIMETHYLSILYL SUBSTITUTED BENZOYL CHLORIDES AND METHOD FOR THE PRODUCTION THEREOF

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3080324A (en) * 1960-08-01 1963-03-05 Cincinnati Milling Machine Co Grignard reagents
US3347897A (en) * 1963-12-24 1967-10-17 Monsanto Res Corp Haloaryl organodisilaalkane compounds and use therefor
US4116993A (en) * 1977-07-05 1978-09-26 General Electric Company Process for producing aromatic-containing silicone compounds
EP0403713A1 (en) * 1989-06-22 1990-12-27 Merrell Dow Pharmaceuticals Inc. Novel acetylcholinesterase inhibitors
EP0409676A1 (en) * 1989-06-22 1991-01-23 Merrell Dow Pharmaceuticals Inc. Novel acetylcholinesterase inhibitors

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Chen, J. G. and Tamborski, J. Organometallic Chemistry, vol. 251, pp. 149 158 (1983). *
Chen, J. G. and Tamborski, J. Organometallic Chemistry, vol. 251, pp. 149-158 (1983).
Odabashyan, G. V. et al., Chemical Abstracts vol. 76, p. 478, 153843W, (1972). *
Ramsden, Hugh E. et al., J. Org. Chem., vol. 22, pp. 1202 1206 (1957). *
Ramsden, Hugh E. et al., J. Org. Chem., vol. 22, pp. 1202-1206 (1957).

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0770618A3 (en) * 1995-10-23 1999-01-20 Dow Corning Corporation Process for preparation of organosilanes
US6380415B2 (en) * 2000-02-14 2002-04-30 Central Glass Company, Limited Process for producing octafluoro[2,2]paracyclophane
KR100979578B1 (en) * 2002-06-13 2010-09-01 다우 코닝 코포레이션 Process for preparing organosilanes and derivatives thereof by a novel Grignard process

Also Published As

Publication number Publication date
AR000246A1 (en) 1997-06-18
JPH11501285A (en) 1999-02-02
WO1996014322A1 (en) 1996-05-17
FI971964A0 (en) 1997-05-07
KR970707134A (en) 1997-12-01
NO972129D0 (en) 1997-05-07
FI971964A7 (en) 1997-05-07
FI971964L (en) 1997-05-07
IL115907A0 (en) 1996-01-31
HUT76927A (en) 1998-01-28
CA2204728A1 (en) 1996-05-17
AU695326B2 (en) 1998-08-13
NO972129L (en) 1997-05-07
ZA959322B (en) 1996-05-29
MX9703368A (en) 1997-08-30
TW349952B (en) 1999-01-11
NZ295530A (en) 1999-02-25
AU3889295A (en) 1996-05-31
EP0791001A1 (en) 1997-08-27

Similar Documents

Publication Publication Date Title
Crowe et al. 2-Metallated Oxazoles; pKa Dependent Deuterations, NMR Studies and Palladium Catalysed Coupling.
JP2525127B2 (en) Enantioselective Oxazaborolidine
US4950767A (en) Process for the preparation of the (-)-antipode of (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene
EP2264005B1 (en) Method for producing optically active cyanohydrin compound
EP0734369B1 (en) Process for preparing intermediates for the synthesis of antifungal agents
US5486638A (en) Process for the preparation of 1-halo-3-trialkysilanyl-benzene derivatives
US4294975A (en) Hydroalkenyloxysilanes
CN112645909A (en) Method for synthesizing alpha-benzyl benzofuran compound
US5760267A (en) Process for preparing 1-(3-trialkylsilylphenyl)-2,2,2-trifluoromethyl ethanone derivatives
US4629801A (en) Preparation of hydrogenosilanes
Thurner et al. A new base promoted rearrangement of (E)-1-benzyloxy-2, 3-epoxyalkanes
Jones et al. Highly diastereoselective reactions using masked allylic zinc reagents
US5723643A (en) Method for the preparation of acryloxy- or methacryloxy-functional organosilicon compounds
US4472313A (en) Cyclopropanation of olefins
MXPA97003368A (en) Procedure for the preparation of 1-halogen-3-trialquilsilanil-benc derivatives
CN111662147B (en) Process for preparing diynes and analogues thereof
US4876363A (en) Epoxy-containing organic silicon compounds
CN119119134B (en) Toothed metal complexes and their preparation methods, and preparation methods of α and β-alkenylsilane compounds.
JPS6212770B2 (en)
US4898959A (en) Method for the preparation of beta-substituted allylsilane
CN107033178B (en) A kind of trimethylsilyl enyne compound and its synthesis method
JPH0768250B2 (en) Method for producing alkylsilyl cyanide
US4677216A (en) 2-Substituted-1,3-butadiene derivatives and process for producing same
WO2022155980A1 (en) METHOD FOR SYNTHESIZING α-BENZYL BENZOFURAN COMPOUND
EP0003866B1 (en) 3-azabicyclo(3.1.0)hexane derivatives and a process for their preparation

Legal Events

Date Code Title Description
AS Assignment

Owner name: MATION MERRELL DOW INC., OHIO

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:DOW CHEMICAL COMPANY, THE;REEL/FRAME:007604/0885

Effective date: 19950119

Owner name: DOW CHEMICAL COMPANY, THE, MICHIGAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KLIPA, DENNIS K.;KEATEN, ROBERT T.;REEL/FRAME:007604/0900

Effective date: 19950119

CC Certificate of correction
FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
FP Lapsed due to failure to pay maintenance fee

Effective date: 20040123

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362